Clostridium perfringens Epsilon Toxin Targets Granule Cells in the Mouse Cerebellum and Stimulates Glutamate Release

Epsilon toxin (ET) produced by C. perfringens types B and D is a highly potent pore-forming toxin. ET-intoxicated animals express severe neurological disorders that are thought to result from the formation of vasogenic brain edemas and indirect neuronal excitotoxicity. The cerebellum is a predilection site for ET damage. ET has been proposed to bind to glial cells such as astrocytes and oligodendrocytes. However, the possibility that ET binds and attacks the neurons remains an open question. Using specific anti-ET mouse polyclonal antibodies and mouse brain slices preincubated with ET, we found that several brain structures were labeled, the cerebellum being a prominent one. In cerebellar slices, we analyzed the co-staining of ET with specific cell markers, and found that ET binds to the cell body of granule cells, oligodendrocytes, but not astrocytes or nerve endings. Identification of granule cells as neuronal ET targets was confirmed by the observation that ET induced intracellular Ca2+ rises and glutamate release in primary cultures of granule cells. In cultured cerebellar slices, whole cell patch-clamp recordings of synaptic currents in Purkinje cells revealed that ET greatly stimulates both spontaneous excitatory and inhibitory activities. However, pharmacological dissection of these effects indicated that they were only a result of an increased granule cell firing activity and did not involve a direct action of the toxin on glutamatergic nerve terminals or inhibitory interneurons. Patch-clamp recordings of granule cell somata showed that ET causes a decrease in neuronal membrane resistance associated with pore-opening and depolarization of the neuronal membrane, which subsequently lead to the firing of the neuronal network and stimulation of glutamate release. This work demonstrates that a subset of neurons can be directly targeted by ET, suggesting that part of ET-induced neuronal damage observed in neuronal tissue is due to a direct effect of ET on neurons

Sex-dependent expression of neutrophil gelatinase-associated lipocalin in aortic stenosis

Background: Accumulating evidence suggest the existence of sex-related differences in the pathogenesis of aortic stenosis (AS) with inflammation, oxidative stress, fibrosis and calcification being over-represented in men. Neutrophil gelatinase-associated lipocalin (NGAL) is expressed in a myriad of tissues and cell types, and it is associated with acute and chronic pathological processes comprising inflammation, fibrosis or calcification. Sex-dependent signatures have been evidenced for NGAL which expression has been associated predominantly in males to metabolic and cardiovascular disorders. We aimed to analyse sex-related differences of NGAL in AS and its role in the inflammatory and fibrocalcific progression of AS. Methods and results: 220 (60.45% men) patients with severe AS elective for surgical aortic valve (AV) replacement were recruited. Immunohistochemistry revealed higher expression of NGAL in calcific areas of AVs and that was validated by qPCR in in 65 (60% men) donors. Valve interstitial cells (VICs) were a source of NGAL in these samples. Proteome profiler analyses evidenced higher expression of NGAL in men compared to women, and that was further validated by ELISA. NGAL expression in the AV was correlated with inflammation, oxidative stress, and osteogenic markers, as well as calcium score. The expression of NGAL, both intracellular and secreted (sNGAL), was significantly deregulated only in calcifying male-derived VICs. Depletion of intracellular NGAL in calcifying male-derived VICs was associated with pro-inflammatory profiles, dysbalanced matrix remodelling and pro-osteogenic profiles. Conversely, exogenous NGAL mediated inflammatory and dysbalanced matrix remodelling in calcifying VICs, and all that was prevented by the pharmacological blockade of NGAL. Conclusions: Owing to the over-expression of NGAL, the AV from men may be endowed with higher expression of inflammatory, oxidative stress, matrix remodelling and osteogenic markers supporting the progression of calcific AS phenotypes. The expression of NGAL in the VIC emerges as a potential therapeutic checkpoint, with its effects being potentially reverted by the pharmacological blockade of extracellular NGAL.This research was funded by Miguel Servet contract CP13/00221 from Instituto de Salud Carlos III-FEDER, Fondo de Investigaciones Sanitarias [PI18/01875; PI21/00280]. M.G. is supported by a Miguel Servet Foundation PhD studentship, E.M.-N is supported by a Margarita Salas postdoctoral fellowship (ULL-MS-P14), L.M. is supported by a PFIS (FI19/00302) PhD studentship, E.J. (CD19/00251) is supported by a Sara Borrell postdoctoral fellowship

Combining Postcards, Crisis Cards, and Telephone Contact Into a Decision-Making Algorithm to Reduce Suicide Reattempt

International audienceBACKGROUND:There is growing evidence in the literature that brief contact interventions (BCIs) might be reliable suicide prevention strategies.OBJECTIVE:To assess the effectiveness of a decision-making algorithm for suicide prevention (ALGOS) combining existing BCIs in reducing suicide reattempts in patients discharged after a suicide attempt.METHODS:A randomized, multicenter, controlled, parallel trial was conducted in 23 hospitals. The study was conducted from January 26, 2010, to February 28, 2013. People who had made a suicide attempt were randomly assigned to either the intervention group (ALGOS) or the control group. The primary outcome was the rate of participants who reattempted suicide (fatal or not) within the 6-month study period.RESULTS:1,040 patients were recruited. After 6 months, 58 participants in the intervention group (12.8%) reattempted suicide compared with 77 (17.2%) in the control group. The difference between groups (4.4%; 95% CI, -0.7% to 9.0%) was not significant (complete-case analysis, P = .059).CONCLUSIONS:These results may help researchers better integrate BCIs into routine health care and provide new insights concerning personalized suicide prevention strategies.TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT01123174

Programa d’optimització d’antibiòtics: infeccions del tracte urinari en adults

Antibiòtics; Infeccions; Tracte urinari; AdultsAntibiotics; Infections; Urinary tract; AdultsAntibióticos; Infecciones; Tracto urinario; AdultosAl document s’hi aborden les principals infeccions del tracte urinari, es descriuen les recomanacions i accions a dur a terme abans de prescriure un antibiòtic i se n’estableixen criteris de tractament, seguiment i derivació